This application is for the continued support of an on-going research project involving human colo-rectal adenocarcinomas, grown both in culture and in mice, which are either immunosuppressed with a new murine anti-thymocyte serum (ATS) produced in goats or immune-deprived by thymectomy, potentially lethal irradiation, and reconstitution with bone marrow from thymectomized, syngeneic donors. Investiqation of the biochemistry of these neoplastic cells is concentrated particularly on (a) target enzymes (especially those critically involed in the salvage of pyrimidine-containing compounds), with a view to rational chemotherapeutic exploitation, (b) the requirements and deficiencies of these neoplastic cells, both in culture and in vivo, in comparison with their normal counterparts and other normal tissues, (c) the mechanisms responsible for the inter-tumor selectivity of 5-fluorouracil and its nucleosides, (d) the role of ATS in the rapid dissemination of neoplastic cells and possibly in true (as well as artificial) metastases of colonic neoplasms, and (e) the study of the chemotherapy of human colo-rectal tumors implanted in (or disseminated into) various loci of the mice. The chemotherapeutic investigations, which will involve both single drugs and combinations of existing agents, are supported by the concurrent synthesis (financially supported otherwise) of new compounds, designed to inhibit key enzymes involved in the salvage by the cancer cells (especially of uracil, uridine and cytidine), and by the study of appropriate compounds obtained from other sources. The over-all objective is the discovery of new chemotherapeutic agents and the rapid translation of any beneficial results obtained with human colo-rectal adenocarcinomas in mice to the treatment of this now relatively drug-insensitive neoplastic disease in man.